Abstract Description

The extracellular matrix (ECM) is a dynamic, three-dimensional network of proteins and carbohydrates located outside cells. The ECM provides structural support and regulates many biological processes, while also playing a role in development, differentiation and acting as a barrier to infection and metastasis. The ECM is dynamic and constantly remodelled in response to environmental cues. Among the ECM components, fibronectin (FN) has emerged as an important therapeutic target. FN is a glycoprotein that is abundant in the ECM and is considered an early scaffolding protein. FN is secreted as a soluble protein and transformed into an insoluble network by cell-mediated unfolding and fibrillogenesis. However, levels must be tightly controlled. High levels of FN expression are linked to cancer invasion and development of fibrosis. Some bacteria target the FN matrix to promote infection. The functional upstream domain (FUD) is an FN-binding peptide derived from the F1 adhesin protein of Streptococcus pyogenes. FUD inhibits fibronectin matrix assembly by binding with high affinity to the N-terminal 70-kDa domain of FN, which reduces the FN barrier to infection. We show that the Hsp90 chaperone binds a similar site on FN to FUD. However, Hsp90 promotes FN assembly promoting matrix deposition and therefore may counteract the effects of FUD and serve to block infection. We report the link between Hsp90 ATPase activity and demonstrate that the affinity of Hsp90 for FN controls FN matrix assembly and hence may be an approach to preventing infection in future.